Despite advances in the care and treatment of hyperbilirubinemia, human newborns are still at risk from brain damage and hearing loss from bilirubin toxicity. The spectrum of bilirubin encephalopathy in human newborns today ranges from "classic kernicterus", still seen in premature, low-birth-weight infants, to more subtle sequelae of isolated hearing loss and cognitive dysfunction. The incidence of impairment due to bilirubin toxicity, especially in the latter, more subtle conditions, is largely unknown because it is difficult to relate abnormalities that show up later in life to transient biochemical abnormalities that occur in the newborn period. Furthermore, the name of the sites of auditory nervous system dysfunction in bilirubin encephalopathy are still unknown and controversial despite decades of study. In a continuation of our successful use of brainstem auditory evoked potentials (BAEPs) in the Gunn rat model of bilirubin encephalopathy, we will extend our efforts to define the time course of auditory dysfunction, the potential for its reversibility, and interaction with developmental processes. These efforts will include comparison of BAEPs with quantitative histology and biochemical assays of unbound neurotoxic bilirubin. Intervention aimed at decreasing bilirubin toxicity, such as exchange transfusion and injection of albumin to transfer bilirubin out of brain tissue, will explore the time constraints of reversibility of the pathological process. BAEP findings occurring soon after acute exposure to bilirubin toxicity will be compared to measurements of free and proteins- bound blood bilirubin, and to histological findings. Studies it rats at different ages will examine the increased vulnerability of the immature central nervous system to bilirubin toxicity. In related studies, we will continue our efforts to localize the specific site(s) of bilirubin-induced auditory nervous system dysfunction utilizing BAEPs and histology assess damage to the cochlea and the auditory brainstem nuclei. The resulting multidisciplinary approach is expected to provide new insights into the pathogenesis of and reversibility of this disorder, and its effects on the auditory system. The understanding of the complex relationship between electrophysiological, anatomical and biochemical processes in animal models of bilirubin encephalopathy should lead to improved noninvasive procedures for predicting neurological and audiological sequelae in human newborns.